This invention relates to novel derivatives of glycyrrhetinic acid and to their use as antiulcer agents. More specifically, it relates to amide derivatives of 18.beta.-glycyrrhetinic acid and its 3-alkanoyl derivatives which are useful antiulcer agents wherein the amide is derived from an amino acid.
Chronic gastric and duodenal ulcers, collectively known as peptic ulcers, are a common affliction for which a variety of treatments have been developed. The treatment depends upon the severity of the ulcer and may range from dietary and medical (drug) treatment to surgery. A wide variety of drugs have been used to treat ulcers, the most recent of which to gain widespread attention is carbenoxolone sodium, the disodium salt of the hemissuccinate of glycyrrhetinic acid. It is reported to prevent formation of and to accelerate healing of gastric ulcers in animals, including humans, ("Carbenoxolone Sodium: A Symposium," J. M. Robson and F. M. Sullivan, Eds., Butterworths, London, 1968). However, its use is accompanied by undesirable aldosterone-like side effects, such as marked antidiuretic and sodium-retaining activity and, oftentimes, potassium loss, such that continued therapy with this agent often leads to hypertension, muscle weakness and, ultimately, congestive heart failure.
Carbenoxolone sodium is almost wholly absorbed in the stomach and is not effective against duodenal ulcers except when administered as a specially formulated capsule which enables its transport to the desired site.
A more effective treatment of peptic ulcers is, therefore, desirable. One which will effectively act upon ulcers in the duodenum, as well as upon gastric ulcers, without the need of special formulation and minimizes the aldosterone-like side effects of carbenoxolone is especially desirable.
Glycyrrhetinic acid, esters, 3-acyloxy derivatives, salts and amides thereof are known to exhibit pharmaceutical properties. British Pat. No. 628,443 (Aug. 14, 1963) reports glycyrrhetinic acid to be an antiinflammatory, analgesic and antipyretic agent. U.S. Pat. No. 3,070,623 (Dec. 25, 1962) described hemi-esters of glycyrrhetinic acid, including the hemisuccinate (also known as carbenoxolone sodium), as anti-inflammatory agents. U.S. Pat. No. 3,070,624 (Dec. 25, 1962) teaches basic esters of the carboxy group at the 20-position of glycyrrhetinic acid which exhibit anti-inflammatory properties and inhibit the action of steroids and steroidal metabolism. Antiinflammatory and analgesic properties are reported for amino acid salts of glycyrrhetinic acid in Japanese Pat. No. 32798/69, published Oct. 27, 1965. French Pat. No. 215 CAM/5544M, published July 19, 1968, discloses hypoglycemic activity for glycyrrhetinic acid and its methyl ester. Salts of glycyrrhetinic acid and its hemi-esters with aluminum, zinc, bismuth and metals of groups II-A and VIII of the Periodic Chart of the Elements are reported in Belgian Pat. No. 628,444, published Feb. 4, 1963, to be of value in treating digestive disorders, such as gastric acidosis, inflammation and ulcers.
Amides of glycyrrhetinic acid and its 3-acyl derivatives useful as anti-inflammatory agents are described in a number of patents. Cyclic amides, e.g., the piperazine, N-acylpiperazides, N-carbalkoxypiperazides, are described in Belgian Pat. No. 753,773, granted July 28, 1969. The N-(lower alkyl)piperazides, piperidide and morpholide are disclosed in Japanese Pat. No. 26,300/67, published Dec. 13, 1967, (C.A. 69, 44067t, 1968). Additionally, simple amides, e.g., the di(lower alkyl)substituted amides, are described in this Japanese Patent. U.S. Pat. No. 3,412,084 (Nov. 19, 1968) teaches alkyl, cycloalkyl, aralkyl and aryl substituted amides of glycyrrhetinic acid as well as heterocyclic amides thereof, all of which are reported to be antiinflammatory agents of low toxicity. Dialkylaminoalkyl substituted amides of glycyrrhetinic acid are described by Adanin et al., Zh. Obshch. Khim. 37, 1063-65 (1967) (C.A. 68, 22087q, 1968). Alkylolamine condensates of glycyrrhetinic acid useful as anti-inflammatory agents in cosmetics are reported in Japanese Pat. No. 8382/67, published Nov. 4, 1967.
A variety of derivatives of glycyrrhetinic acid and 11-deoxoglycyrrhetinic acid are described by Dean et al., J. Pharm. Pharmac. 19, 682-9 (1967); including the hemi-succinates of methyl glycyrrhetinate, glycyrrhetinamide and 11-deoxoglycyrrhetinic acid; the 3-acetyl derivatives of glycyrrhetinamido-ortho- and para-benzoic acids; and N-(glycyrrhetinyl)glycine(glycyrrhetinuric acid).
Various derivatives of 11-deoxoglycyrrhetinic acids useful as intermediates are described by Ruzicka et al. in Helv. Chim. Acta 20, 1271 (1937) and 22, 197 (1939); Corey et al., J. Am. Chem. Soc. 81, 1745 (1959) and Drefahl et al., Ber. 94, 2015 (1961): the acetyl-, the methyl ester, the acetyl-acid chloride, the acetyl methyl ester, the acetyl azide and the acetyl amide.
Groen et al., Acta. Med. Scand. Suppl. 312, 745-748 (1956) in a comparative study of the pharmacological activity of the adrenocortical steroids and glycyrrhetinic acid noted that in order to retain activity in either class of compounds only a limited degree of structural variation is possible. They noted that "the activity seemed dependent on the presence of an 11-keto group." Vinogradov et al., Khim. v Estestn. Naukaki Sb. 40-6, 1965 (C.A. 65, 6136c, 1966) report the methyl ester of 11-deoxoglycyrrhetinic acid gave rise to a sharp increase in the excretion of water and sodium by the kidneys in dogs. In rats, 11-deoxoglycyrrhetinic relieved the action of deoxycorticosterone.